The Experts below are selected from a list of 7413 Experts worldwide ranked by ideXlab platform
Catherine Ledent - One of the best experts on this subject based on the ideXlab platform.
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uncovering caffeine s Adenosine A2A Receptor inverse agonism in experimental parkinsonism
ACS Chemical Biology, 2014Co-Authors: Victor Fernandezduenas, Kenneth A. Jacobson, Jaume Taura, Catherine Ledent, Masahiko Watanabe, Jean-pierre Vilardaga, Maricel Gomezsoler, Marc Lopezcano, Francisco CiruelaAbstract:Caffeine, the most consumed psychoactive substance worldwide, may have beneficial effects on Parkinson’s disease (PD) therapy. The mechanism by which caffeine contributes to its antiparkinsonian effects by acting as either an Adenosine A2A Receptor (A2AR) neutral antagonist or an inverse agonist is unresolved. Here we show that caffeine is an A2AR inverse agonist in cell-based functional studies and in experimental parkinsonism. Thus, we observed that caffeine triggers a distinct mode, opposite to A2AR agonist, of the Receptor’s activation switch leading to suppression of its spontaneous activity. These inverse agonist-related effects were also determined in the striatum of a mouse model of PD, correlating well with increased caffeine-mediated motor effects. Overall, caffeine A2AR inverse agonism may be behind some of the well-known physiological effects of this substance both in health and disease. This information might have a critical mechanistic impact for PD pharmacotherapeutic design.
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Uncovering Caffeine’s Adenosine A2A Receptor Inverse Agonism in Experimental Parkinsonism
ACS chemical biology, 2014Co-Authors: Víctor Fernández-dueñas, Kenneth A. Jacobson, Maricel Gómez-soler, Marc López-cano, Jaume Taura, Catherine Ledent, Masahiko Watanabe, Jean-pierre Vilardaga, Francisco CiruelaAbstract:Caffeine, the most consumed psychoactive substance worldwide, may have beneficial effects on Parkinson’s disease (PD) therapy. The mechanism by which caffeine contributes to its antiparkinsonian effects by acting as either an Adenosine A2A Receptor (A2AR) neutral antagonist or an inverse agonist is unresolved. Here we show that caffeine is an A2AR inverse agonist in cell-based functional studies and in experimental parkinsonism. Thus, we observed that caffeine triggers a distinct mode, opposite to A2AR agonist, of the Receptor’s activation switch leading to suppression of its spontaneous activity. These inverse agonist-related effects were also determined in the striatum of a mouse model of PD, correlating well with increased caffeine-mediated motor effects. Overall, caffeine A2AR inverse agonism may be behind some of the well-known physiological effects of this substance both in health and disease. This information might have a critical mechanistic impact for PD pharmacotherapeutic design.
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Reduced response to the formalin test and lowered spinal NMDA glutamate Receptor binding in Adenosine A2A Receptor knockout mice.
Pain, 2006Co-Authors: Martin Hussey, Catherine Ledent, Geoffrey D. Clarke, Susanna M.o. Hourani, Ian KitchenAbstract:Adenosine is a neuromodulator with complex effects on pain pathways. Mice lacking the Adenosine A2A Receptor are hypoalgesic, and have altered analgesic responses to Receptor-selective opioid agonists. These and other findings suggest a role for the Adenosine A2A Receptor in sensitizing afferent fibres projecting to the spinal cord. To test this hypothesis formalin (20 microl, 5%) was injected into the paw and nociceptive responses were measured in wildtype and Adenosine A2A Receptor knockout mice. There was a significant reduction in nociception associated with sensory nerve activation in the knockout mice as measured by time spent biting/licking the formalin-injected paw and number of flinches seen during the first phase, but only the number of flinches was reduced during the second inflammatory phase. In addition, the selective Adenosine A2A antagonist SCH58261 (3 and 10 mg/kg) also antagonised both phases of the formalin test. We also labelled NMDA glutamate and NK1 Receptors in spinal cord sections as an indirect measure of nociceptive transmission from peripheral sites to the spinal cord. [3H]-Substance P binding to NK1 Receptors was unaltered but there was a substantial reduction in binding of [3H]-MK801 to NMDA glutamate Receptors in all regions of the spinal cord from knockout mice. The decrease in NMDA glutamate Receptor binding may reflect reduced peripheral sensory input to the spinal cord during development and could relate to the hypoalgesia in this genotype. These results support a key role for the Adenosine A2A Receptor in peripheral nociceptive pathways.
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Characterisation of central Adenosine A1 Receptors and Adenosine transporters in mice lacking the Adenosine A2A Receptor
Brain Research, 2000Co-Authors: Broughton J Snell, Catherine Ledent, Jennifer L. Short, John Drago, Andrew J. LawrenceAbstract:Abstract The present study was designed to assess whether Adenosine A2A Receptor knockout mice exhibit altered purine utilisation in brain nuclei. Specifically, the properties of Adenosine transporters and Adenosine A1 Receptors were characterised in brain membranes and on slide-mounted sections. The BMAX for [3H]nitrobenzylthioinosine ([3H]NBTI) binding (Adenosine transporter density) was significantly reduced in brainstem membranes of homozygotes (560±52 fmol/mg protein, n=5, P
Irving L Kron - One of the best experts on this subject based on the ideXlab platform.
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ex vivo lung perfusion with Adenosine A2A Receptor agonist allows prolonged cold preservation of lungs donated after cardiac death
The Journal of Thoracic and Cardiovascular Surgery, 2016Co-Authors: Cynthia E Wagner, Nicolas H Pope, Eric J Charles, Mary E Huerter, Ashish Sharma, Morgan Salmon, Benjamin T Carter, Mark H Stoler, Victor E Laubach, Irving L KronAbstract:Abstract Objective Ex vivo lung perfusion has been successful in the assessment of marginal donor lungs, including donation after cardiac death (DCD) donor lungs. Ex vivo lung perfusion also represents a unique platform for targeted drug delivery. We sought to determine whether ischemia-reperfusion injury would be decreased after transplantation of DCD donor lungs subjected to prolonged cold preservation and treated with an Adenosine A2A Receptor agonist during ex vivo lung perfusion. Methods Porcine DCD donor lungs were preserved at 4°C for 12 hours and underwent ex vivo lung perfusion for 4 hours. Left lungs were then transplanted and reperfused for 4 hours. Three groups (n = 4/group) were randomized according to treatment with the Adenosine A2A Receptor agonist ATL-1223 or the dimethyl sulfoxide vehicle: Infusion of dimethyl sulfoxide during ex vivo lung perfusion and reperfusion (DMSO), infusion of ATL-1223 during ex vivo lung perfusion and dimethyl sulfoxide during reperfusion (ATL-E), and infusion of ATL-1223 during ex vivo lung perfusion and reperfusion (ATL-E/R). Final Pao 2 /Fio 2 ratios (arterial oxygen partial pressure/fraction of inspired oxygen) were determined from samples obtained from the left superior and inferior pulmonary veins. Results Final Pao 2 /Fio 2 ratios in the ATL-E/R group (430.1 ± 26.4 mm Hg) were similar to final Pao 2 /Fio 2 ratios in the ATL-E group (413.6 ± 18.8 mm Hg), but both treated groups had significantly higher final Pao 2 /Fio 2 ratios compared with the dimethyl sulfoxide group (84.8 ± 17.7 mm Hg). Low oxygenation gradients during ex vivo lung perfusion did not preclude superior oxygenation capacity during reperfusion. Conclusions After prolonged cold preservation, treatment of DCD donor lungs with an Adenosine A2A Receptor agonist during ex vivo lung perfusion enabled Pao 2 /Fio 2 ratios greater than 400 mm Hg after transplantation in a preclinical porcine model. Pulmonary function during ex vivo lung perfusion was not predictive of outcomes after transplantation.
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transplantation lungex vivo lung perfusion with Adenosine A2A Receptor agonist allows prolonged cold preservation of lungs donated after cardiac death
The Journal of Thoracic and Cardiovascular Surgery, 2016Co-Authors: Cynthia E Wagner, Nicolas H Pope, Eric J Charles, Mary E Huerter, Ashish Sharma, Morgan Salmon, Benjamin T Carter, Mark H Stoler, Victor E Laubach, Irving L KronAbstract:Objective Ex vivo lung perfusion has been successful in the assessment of marginal donor lungs, including donation after cardiac death (DCD) donor lungs. Ex vivo lung perfusion also represents a unique platform for targeted drug delivery. We sought to determine whether ischemia-reperfusion injury would be decreased after transplantation of DCD donor lungs subjected to prolonged cold preservation and treated with an Adenosine A2A Receptor agonist during ex vivo lung perfusion.
Francisco Ciruela - One of the best experts on this subject based on the ideXlab platform.
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uncovering caffeine s Adenosine A2A Receptor inverse agonism in experimental parkinsonism
ACS Chemical Biology, 2014Co-Authors: Victor Fernandezduenas, Kenneth A. Jacobson, Jaume Taura, Catherine Ledent, Masahiko Watanabe, Jean-pierre Vilardaga, Maricel Gomezsoler, Marc Lopezcano, Francisco CiruelaAbstract:Caffeine, the most consumed psychoactive substance worldwide, may have beneficial effects on Parkinson’s disease (PD) therapy. The mechanism by which caffeine contributes to its antiparkinsonian effects by acting as either an Adenosine A2A Receptor (A2AR) neutral antagonist or an inverse agonist is unresolved. Here we show that caffeine is an A2AR inverse agonist in cell-based functional studies and in experimental parkinsonism. Thus, we observed that caffeine triggers a distinct mode, opposite to A2AR agonist, of the Receptor’s activation switch leading to suppression of its spontaneous activity. These inverse agonist-related effects were also determined in the striatum of a mouse model of PD, correlating well with increased caffeine-mediated motor effects. Overall, caffeine A2AR inverse agonism may be behind some of the well-known physiological effects of this substance both in health and disease. This information might have a critical mechanistic impact for PD pharmacotherapeutic design.
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Uncovering Caffeine’s Adenosine A2A Receptor Inverse Agonism in Experimental Parkinsonism
ACS chemical biology, 2014Co-Authors: Víctor Fernández-dueñas, Kenneth A. Jacobson, Maricel Gómez-soler, Marc López-cano, Jaume Taura, Catherine Ledent, Masahiko Watanabe, Jean-pierre Vilardaga, Francisco CiruelaAbstract:Caffeine, the most consumed psychoactive substance worldwide, may have beneficial effects on Parkinson’s disease (PD) therapy. The mechanism by which caffeine contributes to its antiparkinsonian effects by acting as either an Adenosine A2A Receptor (A2AR) neutral antagonist or an inverse agonist is unresolved. Here we show that caffeine is an A2AR inverse agonist in cell-based functional studies and in experimental parkinsonism. Thus, we observed that caffeine triggers a distinct mode, opposite to A2AR agonist, of the Receptor’s activation switch leading to suppression of its spontaneous activity. These inverse agonist-related effects were also determined in the striatum of a mouse model of PD, correlating well with increased caffeine-mediated motor effects. Overall, caffeine A2AR inverse agonism may be behind some of the well-known physiological effects of this substance both in health and disease. This information might have a critical mechanistic impact for PD pharmacotherapeutic design.
Cynthia E Wagner - One of the best experts on this subject based on the ideXlab platform.
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ex vivo lung perfusion with Adenosine A2A Receptor agonist allows prolonged cold preservation of lungs donated after cardiac death
The Journal of Thoracic and Cardiovascular Surgery, 2016Co-Authors: Cynthia E Wagner, Nicolas H Pope, Eric J Charles, Mary E Huerter, Ashish Sharma, Morgan Salmon, Benjamin T Carter, Mark H Stoler, Victor E Laubach, Irving L KronAbstract:Abstract Objective Ex vivo lung perfusion has been successful in the assessment of marginal donor lungs, including donation after cardiac death (DCD) donor lungs. Ex vivo lung perfusion also represents a unique platform for targeted drug delivery. We sought to determine whether ischemia-reperfusion injury would be decreased after transplantation of DCD donor lungs subjected to prolonged cold preservation and treated with an Adenosine A2A Receptor agonist during ex vivo lung perfusion. Methods Porcine DCD donor lungs were preserved at 4°C for 12 hours and underwent ex vivo lung perfusion for 4 hours. Left lungs were then transplanted and reperfused for 4 hours. Three groups (n = 4/group) were randomized according to treatment with the Adenosine A2A Receptor agonist ATL-1223 or the dimethyl sulfoxide vehicle: Infusion of dimethyl sulfoxide during ex vivo lung perfusion and reperfusion (DMSO), infusion of ATL-1223 during ex vivo lung perfusion and dimethyl sulfoxide during reperfusion (ATL-E), and infusion of ATL-1223 during ex vivo lung perfusion and reperfusion (ATL-E/R). Final Pao 2 /Fio 2 ratios (arterial oxygen partial pressure/fraction of inspired oxygen) were determined from samples obtained from the left superior and inferior pulmonary veins. Results Final Pao 2 /Fio 2 ratios in the ATL-E/R group (430.1 ± 26.4 mm Hg) were similar to final Pao 2 /Fio 2 ratios in the ATL-E group (413.6 ± 18.8 mm Hg), but both treated groups had significantly higher final Pao 2 /Fio 2 ratios compared with the dimethyl sulfoxide group (84.8 ± 17.7 mm Hg). Low oxygenation gradients during ex vivo lung perfusion did not preclude superior oxygenation capacity during reperfusion. Conclusions After prolonged cold preservation, treatment of DCD donor lungs with an Adenosine A2A Receptor agonist during ex vivo lung perfusion enabled Pao 2 /Fio 2 ratios greater than 400 mm Hg after transplantation in a preclinical porcine model. Pulmonary function during ex vivo lung perfusion was not predictive of outcomes after transplantation.
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transplantation lungex vivo lung perfusion with Adenosine A2A Receptor agonist allows prolonged cold preservation of lungs donated after cardiac death
The Journal of Thoracic and Cardiovascular Surgery, 2016Co-Authors: Cynthia E Wagner, Nicolas H Pope, Eric J Charles, Mary E Huerter, Ashish Sharma, Morgan Salmon, Benjamin T Carter, Mark H Stoler, Victor E Laubach, Irving L KronAbstract:Objective Ex vivo lung perfusion has been successful in the assessment of marginal donor lungs, including donation after cardiac death (DCD) donor lungs. Ex vivo lung perfusion also represents a unique platform for targeted drug delivery. We sought to determine whether ischemia-reperfusion injury would be decreased after transplantation of DCD donor lungs subjected to prolonged cold preservation and treated with an Adenosine A2A Receptor agonist during ex vivo lung perfusion.
Osamu Hayaishi - One of the best experts on this subject based on the ideXlab platform.
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an Adenosine A2A Receptor agonist induces sleep by increasing gaba release in the tuberomammillary nucleus to inhibit histaminergic systems in rats
Journal of Neurochemistry, 2005Co-Authors: Zongyuan Hong, Yoshihiro Urade, Naomi Eguchi, Weimin Qu, Zhili Huang, Osamu HayaishiAbstract:The Adenosine A2A Receptor (A2AR) has been demonstrated to play a crucial role in the regulation of the sleep process. However, the molecular mechanism of the A2AR-mediated sleep remains to be elucidated. Here we used electroencephalogram and electromyogram recordings coupled with in vivo microdialysis to investigate the effects of an A2AR agonist, CGS21680, on sleep and on the release of histamine and GABA in the brain. In freely moving rats, CGS21680 applied to the subarachnoid space underlying the rostral basal forebrain significantly promoted sleep and inhibited histamine release in the frontal cortex. The histamine release was negatively correlated with the amount of non-rapid eye movement sleep (r = − 0.652). In urethane-anesthetized rats, CGS21680 inhibited histamine release in both the frontal cortex and medial pre-optic area in a dose-dependent manner, and increased GABA release specifically in the histaminergic tuberomammillary nucleus but not in the frontal cortex. Moreover, the CGS21680-induced inhibition of histamine release was antagonized by perfusion of the tuberomammillary nucleus with a GABAA antagonist, picrotoxin. These results suggest that the A2AR agonist induced sleep by inhibiting the histaminergic system through increasing GABA release in the tuberomammillary nucleus.
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Strong rebound of wakefulness follows prostaglandin D2- or Adenosine A2A Receptor agonist-induced sleep.
Journal of Sleep Research, 2000Co-Authors: Dmitry Gerashchenko, Yoshihiro Urade, Yasuhisa Okano, Shojiro Inoué, Osamu HayaishiAbstract:SUMMARY We studied the effect of sleep excess on the sleep-wakefulness pattern of rats. Subarachnoid infusion of prostaglandin D2 or the Adenosine A2A Receptor agonist CGS21680 effectively induced slow wave sleep (SWS) for the first 12 h of the night-time period, whereas they did not induce sleep during the following 24 h of infusion. An increase in the amount of wakefulness was seen during the last 12 h of prostaglandin D2 infusion. The amounts of wakefulness strongly increased during the following 36-h recovery period. Rebound wakefulness was extraordinarily strong after the cessation of CGS21680 infusion, reaching almost complete insomnia during the night-time. Treatment of animals with prostaglandin D2 overnight, following by treatment with CGS21680 on the next night, resulted in the strongest induction of wakefulness rebound. During the rebound period, the amount of wakefulness reached up to 50 min per hour in the daytime. Rebound of wakefulness depended on the amounts of preceding SWS induced by infusion of prostaglandin D2 for 6 or 12 h and of CGS21680 for 12 h. The larger the amount of SWS, the larger the amount of the following rebound of wakefulness. Rebounds of wakefulness occurred as a result of decrease in SWS amounts, whereas paradoxical sleep amounts did not change. Desensitization of Adenosine A2A Receptors and accumulation of prostaglandin E2 may be involved in the production of strong wakefulness rebound following relatively long treatments (more than 12 h) with prostaglandin D2 or CGS21680.
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region dependent difference in the sleep promoting potency of an Adenosine A2A Receptor agonist
European Journal of Neuroscience, 1999Co-Authors: Shinsuke Satoh, Hitoshi Matsumura, Nobuyo Koike, Yoshimitsu Tokunaga, Toshihiro Maeda, Osamu HayaishiAbstract:The present study has demonstrated that the sleep-promoting potency of 2-[p-(2-carboxyethyl)phenethylamino]-5′-N-ethylcarboxamido Adenosine (CGS21680), a selective agonist for the Adenosine A2A Receptor, varies depending on the location of the administration. CGS21680 was continuously administered to rats through a chronically implanted cannula for 6 h during their active phase. The tip of the cannula was located in the subarachnoid space or the brain ventricle neighbouring the established brain areas implicated in the regulation of sleep–wake phenomena, i.e. rostral basal forebrain, medial preoptic area, lateral preoptic area, posterior hypothalamus, and dorsal tegmentum of the pons and medulla. At an infusion rate of 2.0 pmol/min, the magnitude of increase in non-rapid eye movement sleep varied from 14 min (a 15% increase) to 96 min (a 103% increase), and those of rapid eye movement sleep varied from 6 min (a 40% increase) to 28 min (a 264% increase) from the respective baseline values. The largest increases in both types of sleep occurred when CGS21680 was administered to the subarachnoid space underlying the rostral basal forebrain. These findings were interpreted to mean that the major, if not the only, site responsible for the CGS21680-inducing sleep was located in or near the rostral basal forebrain. This interpretation was supported by the findings that the administration of CGS21680 to the rostral basal forebrain produced predominant expression of Fos within the shell of the nucleus accumbens and the medial portion of the olfactory tubercle, and that the microdialysis perfusion of CGS21680 into the shell of the nucleus accumbens also exhibited a sleep-promoting effect.
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Involvement of Adenosine A2A Receptor in sleep promotion
European journal of pharmacology, 1998Co-Authors: Shinsuke Satoh, Hitoshi Matsumura, Osamu HayaishiAbstract:We examined the sleep-modulatory effects of four Adenosine agonists, namely, (1) 2-(4-(2-carboxyethyl)phenylethylamino)Adenosine-5'-N-ethylcarbo xamideAdenosine (CGS21680), a highly selective Adenosine A2A Receptor agonist; (2) 2-(4-(2-(2-aminoethylaminocarbonyl)ethyl)phenylethylamino)-5 '-N-ethylcarboxamidoAdenosine (APEC), a selective Adenosine A2A Receptor agonist; (3) 5'-N-ethylcarboxamidoAdenosine (NECA), a nonselective Adenosine A1/A2 Receptor agonist, and (4) N6-cyclopentylAdenosine (CPA), a selective Adenosine A1 Receptor agonist. Each agonist was administered in the subarachnoid space underlying the rostral basal forebrain of rats through chronically implanted cannulae at the rate of 0.02, 0.2, 2.0, 12.0, or 20.0 pmol/min over a 6-h period starting from 2300 h, which period is the active phase of the animals. CGS21680, APEC, and NECA produced significant increases in the total amounts of non-rapid-eye-movement (NREM) sleep and rapid-eye-movement (REM) sleep after at least one dose within the range of administration rates. CPA did not produce any significant increase in the total amount of either type of sleep at any of the above administration rates, but instead suppressed REM sleep at the administration rates of 12.0 and 20.0 pmol/min. These results indicate that the activities of Adenosine A2A Receptors are crucially involved in the promotion of sleep.
